Is TCHH p.Gln331Ter (c.991C>T) pathogenic?

TCHH p.Gln331Ter (c.991C>T) is classified Likely pathogenic in TCHH (ClinVar, Single submitter, 2 submitters; last evaluated 2018-03-27). Ultra-rare (popmax 0.0482%, amr); Associated with uncombable hair syndrome 3.

What condition is associated with TCHH p.Gln331Ter (c.991C>T)?

TCHH p.Gln331Ter (c.991C>T) is associated with uncombable hair syndrome 3 (ClinVar).

How common is TCHH p.Gln331Ter (c.991C>T) in the general population?

TCHH p.Gln331Ter (c.991C>T) is ultra-rare (popmax 0.0482%, amr) (gnomAD).

How is Uncombable hair syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

TCHH p.Gln331Ter

c.991C>T · rs201930497 · VCV374835

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0482%, amr)

Conditions

uncombable hair syndrome 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (3 of 3) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.9	GERP -2
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0482% Admixed American · 26/53,956 alleles

Filtering AF 0.0428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0415%

Overall 0.038% 594/1,565,022 alleles · ultra-rare exomes 530/1,444,114 · genomes 64/120,908 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0482%	2,075
European (non-Finnish)	0.046%	2,172
Remaining individualsnot grpmax-eligible	0.0343%	2,915
Finnishnot grpmax-eligible	0.011%	9,055
African / African-American	0.00762%	13,122

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: TCHH
Protein: p.Gln331Ter
Coding: c.991C>T
MANE Select: NM_007113
dbSNP: rs201930497
Type: single nucleotide variant
Location: chr1:152112226 (GRCh38)
Gene constraint: LOEUF 1.811 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.96
Residue 331: the '5 x 13 aa tandem repeats of r-r-e-q-e-e-e-r-r-e-q-q-l' region

Full TCHH gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

uncombable hair syndrome 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Uncombable hair syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

TCHH p.Arg385fs Likely pathogenic ★ same condition
TCHH p.Gln234fs Likely pathogenic ★ same condition
TCHH p.Leu419fs Uncertain significance ★ same condition
TCHH p.Phe1416fs Uncertain significance ★ same condition
TCHH p.Glu626Gly Uncertain significance ★★ ⚠ same type
TCHH p.Ala686Gly Benign ★★ same type
TCHH p.Arg1444Pro Likely benign ★★ ⚠ same type
TCHH p.Arg1876Gln Likely benign ★★ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/tchh-p-gln331ter (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown